Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting the motor neurons of the brain stem and spinal cord. In the United States, 1 of every 1000 deaths is due to ALS. The etiology of ALS remains unclear, although genetic factors are involved in the familial form (10% of cases). Approximately 20% of familial cases have mutations in the gene for Cu/Zn superoxide dismutase (SOD). Oxidative stress may also play a role in sporadic ALS, although SOD mutations are rarely found in this form of the disease. Environmental exposures have also been considered as potential causes of ALS. Previous evidence most clearly suggested a role for exposure to heavy metals, particularly lead, although electromagnetic fields and chemical exposures including pesticides and solvents have also been implicated. We conducted a case-control study of ALS in New England. Specific aims were to characterize potential associations of ALS with (i) lead exposure; (ii) exposure to other neurotoxins, eg, mercury, solvents and pesticides; (iii) lifestyle factors such as cigarette smoking and diet; and (iv) genetic polymorphisms affecting neurologic function or lead metabolism. Cases (N=109) were recruited at two hospitals in Boston, MA. Population controls (N=256) identified by random digit dialing were frequency matched to cases by age, sex, and region of residence within New England. We collected information on occupational, residential, and recreational exposure to lead using a structured interview. In addition, we measured blood and bone lead levels, the latter using in vivo K x-ray fluorescence (K-XRF), and archived whole blood and serum samples for studies of gene-environment interaction. We have explored the relationship of ALS to several lifestyle factors. Cigarette smoking was associated with 1.7-fold increase in ALS risk, but alcohol use had no relationship to ALS. Family history of ALS was also associated with increased risk. We examined dietary intake of calcium, magnesium, and antioxidants. Overall, these dietary factors were not related to ALS risk, although modestly protective associations were suggested for magnesium and lycopene. Analyses of the relationship of ALS to lead exposure found that risk of ALS was associated with a 1.9-fold increase in self-reported occupational exposure to lead, with a dose-response for lifetime days of lead exposure. Risk of ALS was also associated with elevations in both blood and bone lead levels: it was increased 1.9-fold for each mg/dl increase in blood lead, 3.6-fold for each unit increase in log-transformed patella lead, and 2.3-fold for each unit increase in log-transformed tibia lead. These results extend previous reports based entirely on interview data, showing for the first time an association of ALS with lead biomarkers, and suggest a potential role for lead exposure in the etiology of ALS. We have explored the role of genetic susceptibility to lead exposure. Specifically, we evaluated the relationship of ALS to polymorphisms in the genes for delta-aminolevulinic acid dehydratase (ALAD) and the vitamin D receptor (VDR), which have both been implicated in lead susceptibility. The ALAD 2 allele was associated with decreased lead levels in both patella and tibia, although not in blood, and with 1.9-fold increase in ALS risk. In contrast, the VDR B allele was not associated with lead levels or ALS risk. These novel findings suggest that genetic susceptibility conferred by polymorphisms in ALAD may affect ALS risk, possibly through a mechanism related to internal lead exposure. A recent analysis explored the relationship of ALS to vascular endothelial growth factor (VEGF), an angiogenic growth factor that mediates responses to hypoxia. We confirmed previous reports that risk of ALS is associated with polymorphisms in the VEGF promoter region that determine two specific haplotypes. These findings suggest that the mechanism of ALS pathogenesis may involve impaired response to hypoxia. Several additional analyses are in progress. We are investigating the relationship of ALS to polymorphisms in DNA repair enzymes and serum protein profiles. We have conducted a search of the National Death Index to identify dates of death for ALS cases to determine whether lead exposure affects prognosis. Finally, we are analyzing questionnaire data on physical trauma.